ABSTRACT The goal of these studies is to understand the impact of advanced age on opiate modulation of persistent pain. In 2013, people aged 65 and older represented 14.1% of the US population. These numbers are expected to rise dramatically, with person?s aged 65 years or older accounting for 20- 30% of the total population by 2030. Unfortunately, one of the consequences of increased longevity is pain, with 45-85% of the population aged 65 or older experiencing pain on a daily basis. Unfortunately, chronic pain is under-treated for the majority of elderly persons. A primary factor contributing to the under management of pain is the dearth of knowledge on the impact of age on pain and opiate sensitivity. Indeed, a recent consensus statement issued by a multidisciplinary group of pain experts states: ?The paucity of guidelines for opioid use in the elderly reflects the lack of studies of these drugs on the old.? A clear understanding of age-associated changes in opioidergic circuits of males and females is critical for evidence-based pain management in this population. Our behavioral data indicate that the antihyperalgesic effect of morphine is significantly attenuated in aged (18-24 mos) versus adult (2-3 mos) rats. Indeed, the ED50 dose for aged animals is 7.0 mg/kg in comparison to 3.5 mg/kg for adults. Our overarching hypothesis is that age- induced changes in mu opioid receptor expression and signaling within the midbrain periaqueductal gray (PAG) provide the biological bases for the decreased sensitivity to opiates observed in the elderly. Three specific aims are proposed to determine the influence of advanced age on mu opioid receptor expression and receptor pharmacodynamics (SA1) and G protein receptor coupling and regulation (SA2). Aim 3 will use molecular and pharmacological techniques to boost central MOR signaling, thereby reducing morphine dosing requirements. Together, these studies will provide novel and critical data on the impact of age on opiate effectiveness, and will stimulate evidence-based therapies for the management of pain in the elderly.